Inbong Memorial Lecture : Thymic stromal lymphopoietin downregulates filaggrin expression by STAT3 and ERK phosphorylation in keratinocytes

A number of recent studies support the fact that filaggrin is a critical barrier protein. For instance, murine models of filaggrin haploinsufficiency promote a barrier defect and percutaneous allergen sensitization. Loss-of-function mutations of the filaggrin gene (FLG) in human skin strongly predispose ichthyosis vulgaris and atopic dermatitis (AD). Although the frequency and the genetic spectrum of FLG mutations are distinct in each population, approximately 25-50% of patients with AD have been reported to carry FLG mutations. However, all the patients with AD have skin barrier defect. Furthermore, one study showed that the acute lesional skin of patients with AD with the FLG mutation exhibited lower levels of filaggrin expression compared with the nonlesional skin in the same patient. In another report, the authors noted that while there is no correlation between FLG mutations and psoriasis, decreased filaggrin expression has been detected in psoriatic skin, especially in acute plaques. The researchers focused on these observations and anticipated that there should be additional mechanisms to modulate filaggrin expression. We were more concerned with thymic stromal lymphopoietin (TSLP) and its main source, keratinocytes, because TSLP is the initiating key molecule in immunopathogenesis of AD. TSLP is an IL-7-like cytokine which activates myeloid dendritic cells to induce an inflammatory Th2 response. TSLP is highly expressed in acute and chronic AD lesions mainly by keratinocytes in human skin. There are a number of evidences to prove that TSLP is crucial in development of AD. Keratinocytes and its product, TSLP are in the middle of the pathogenesis of atopic inflammation from the very early stage. However, the effects of TSLP on human keratinocytes remain unknown. The aim of this study was to investigate whether TSLP can modulate filaggrin expression in keratinocytes. In this study, we demonstrated the presence of TSLP receptor in human keratinocytes and skin. We also found that filaggrin expression was significantly reduced by TSLP in human keratinocytes and this process was mediated by STAT3- and/or ERK1/2-dependent signaling pathways. These results suggest that TSLP and the related downstream molecules might be a target to ameliorate the disrupted barrier in patients with AD.